One of the classical clinical symptoms of diabetes is increased blood glucose (hyperglycemia), which may be related to polyuria, polydipsia, polyphagia, weight loss, and blurred vision. The long term complications of untreated or ineffectively treated diabetes include retinopathy, nephropathy, and peripheral neuropathy. Diabetic patients have an increased risk of cardiovascular disease and stroke.
Most diabetic patients fall into one of two categories, based on the mechanism of the pathology. Type 1 diabetics suffer from an absolute deficiency of insulin secretion. The insulin deficiency may be related to an autoimmune process destroying the beta cells of the pancreas. Type 2 diabetics, which comprise 90-95% of all diabetic patients, suffer from insulin resistance. In type 2 diabetics, the insulin resistance may be coupled with the inability of the pancreas to adequately respond with sufficient insulin to compensate for the resistance. In both types of diabetes, the failure of the pancreas to provide an appropriate level of insulin secretion results in the disease. New case reports of type 2 diabetes appear to be increasing at an alarming rate in several Western countries and in developing countries as well. In the United States, for example, it is estimated that approximately five per cent of the adult population suffers from some form of diabetic condition, with the rate of newly diagnosed patients increasing at about 6 per cent per year, or approximately 600,000 new cases each year. The treatment and management of type 2 diabetes requires special dietary measures and, often, the use of a pharmaceutical hypoglycemic agent.
An additional, not yet well defined patient population exhibits preclinical symptoms of diabetic conditions, such as impaired glucose tolerance (IGT). IGT is a condition in which plasma glucose levels during an oral glucose tolerance test are above normal, but below those considered as diagnostic for diabetes. This population is estimated to be in the range of 20 to 22 million people in the United States and remains untreated at this time. Edelman SV: Impaired glucose tolerance: a precursor of type 2 or a separate disease entity in itself? Diabetes News 26:1-5, 1995.
There are currently four chemically distinct families of oral hypoglycemic agents used in the management of type 2 diabetes. The first family of agents, the biguanides, primarily suppress excessive hepatic glucose production. The second family, the sulfonylureas, primarily stimulate the pancreas to secrete insulin. Various sulfonylurea agents are presently sold under approximately 100 different brand names. Sulfonylureas, however, fail to control hypoglycemia on initial use in approximately 30 to 40 percent of new cases (primary failures). In an additional 1 to 5 percent of the new cases, sulfonylurea agents eventually lose their effectiveness (secondary failures). The third family consists of alpha glucosidase inhibitors, which delay the absorption of carbohydrates in the small intestine, thus improving postprandial glucose values. The thiazolidinediones are the fourth and newest class of anti-diabetic agents to be approved by the FDA for the treatment of type 2 diabetes. Thiazolidinediones modulate peripheral insulin resistance in skeletal muscle without stimulating insulin secretion. They also, to a lesser degree, reduce excessive hepatic glucose production. All of these oral hypoglycemic agents have undesirable, and potentially serious, side effects.
There are many natural products which appear to exhibit hypoglycemic activity.
These products are generally plants or plant-derived compounds, usually in the form of a crude extract. It is estimated that more than 200 species of plants exhibit hypoglycemic properties, including many common plants, such as immature bean pods, olive leaves, potatoes, wheat, celery, blackbeny leaves, sugar beets, and the leaves and roots of bananas. Farnsworth and Segelman, Tile Till 57:52-55, 1971. Natural hypoglycemic agents have also been isolated, for example, from the leaves of Aloe Aboraescens Var Natalis (Hikino et al, Int. J. Crude Drug Res. 24:183-186, 1986) and from the roots of Oryza sativa (Hikino et al, Planta Med. 490-492, 1986).
The seeds of Eugenia jambolana, a plant found in India, appear to exhibit hypoglycemic activity comparable to that of chlorpropamide, as determined by effects on cathepsin B (Bansal et al, Indian J. Biochem. Biophysic. 18:377, 1981). Further, it has been reported that Salvia lavandulifolia possess a slight hypoglycemic activity that is independent of the effects of insulin (Jimenez et al, Planta Med. 1:260-262, 1986). Other folklore remedies, including tea made from herbs such as Allofylus edulis (Barboza et al, Plantas que Curan 1985), Daucus carota and Cantharanthus roseus, have been sold for the control of diabetes in South American or Southeast Asian countries.
The leaves of Gymnema sylvestre, an herb belonging to the Asclepiadaceae family, have been used by traditional medical practitioners of India to treat diabetic conditions for several centuries. Gymnema sylvestre has also been studied for its anti-sweet properties, for its ability to inhibit small intestine absorption of glucose, and for its ability to suppress increases in blood glucose levels following glucose administration. In the early 1980's, Shanmugasundaram et al showed that the administration of a dried leaf powder of Gymnema sylvestre helped regulate the blood sugar of alloxan diabetic rabbits. Journal of Ethnopharmacology, 7 (1983) pp. 205-234. The authors speculated that the dried leaf caused an increase in insulin output by the already existing beta cells.
In the Indian Journal of Experimental Biology, Vol 19, August 1981, pp 715-721, Shanmugasundaram et al describe an extract of Gymnema sylvestre, GS2, and its hypoglycemic activity at one tenth the dose of the dried leaves of Gymnema sylvestre. At that time, the authors attributed the effect of the extract GS2 to the increased availability of insulin and to the facilitation of metabolites in insulin-dependent processes. In a series of articles published in the Journal of Ethnopharmacology in 1990, Shanmugasundaram et al. demonstrated that additional extracts from the leaves of Gymnema sylvestre, denominated GS3 and GS4, were able to increase the islet number and beta cell number in diabetic rats. GS4 treatment resulted in a significant reduction in blood glucose, glycosylated hemoglobin and glycosylated plasma proteins, as well as decreases in lipid levels. Both extracts, GS3, and GS4, when administered orally to streptozotocin-induced diabetic rats, caused fasting blood glucose levels to return to normal.
Others have reported in the scientific literature hypoglycemic gymnemic acid constituents from Gymnema sylvestre (Murakami et al, Liu et al, Rao et al, Sinsheimer et al). These authors generally report on the ability of the gymnemic acid constituents to inhibit glucose absorption in the small intestine, but have not observed any effect of such compositions on pancreatic tissues.
U.S. Pat. No. 4,761,286 discloses the use of an extract of Gymnema sylvestre to inhibit intestinal glucose absorption, thereby decreasing the amount of caloric intake and preventing obesity. This patent discloses that the amount of glucose absorbed will be substantially less than otherwise anticipated when an extract of Gymnema sylvestre is added to the foodstuff. U.S. Pat. No. 4,912,089 discloses that a purified extract of Gymnema sylvestre inhibits the production of a polysaccharide which is important in the production of plaque implicated in the production of dental caries. This patent teaches the use of purified gymnemic acid as a method of preventing dental caries and does not disclose its use in the prevention or treatment of diabetes. U.S. Pat. No. 5,612,039 discloses adding a dry extract of leaves of Gymnema sylvestre to a weight loss composition, but does not discuss the treatment or prevention of diabetes.
An ideal medication for the treatment and prevention of diabetes would be one which would incorporate the following characteristics: ability to stimulate regeneration of pancreatic islets and beta cells responsible for insulin production and to increase c-peptide levels; ability to modulate the autoimmune destruction of the cells responsible for insulin production; ability to correct the dislipidemia associated with diabetes; ability to decrease insulin resistance; and few or no serious side effects. None of the pharmaceutical compositions for treating diabetes meet all of these criterion.
Existing pharmaceutical oral hypoglycemic agents produce inconsistent clinical results, as well as frequent severe side effects. There is a need in the art for safe and effective oral hypoglycemic agents that provide the clinician with a wider range of options for preventing, treating and managing diabetes. In addition, there is a pressing need for an oral hypoglycemic agent which reverses the loss of functional pancreatic islet cells, including beta cells, responsible for insulin synthesis by stimulating the regeneration of these islet cells, including the beta cells, in patients who suffer from type 1 or type 2 diabetes, as well as IGT.